Anti-cancer therapy, such as the administration of chemotherapeutic agents, is associated with Adverse Events including chemotherapy-associated toxicities. Chemotherapy-associated toxicities include, for example, neurotoxicity, nephrotoxicity, ototoxicity, allergic or hypersensitivity reactions, hepatic toxicity, myelosuppression, as well as other toxicities.
Chemotherapy-associated toxicities can materially offset or limit the potential benefits to the patient undergoing treatment. By way of non-limiting example, chemotherapy-associated toxicity can result in treatment delays, treatment interruptions, dose modifications, dose schedule modifications, or even complete cessation of treatment. Thus, in addition to their adverse pharmacological affects, the development of chemotherapy-associated toxicities can limit or curtail the effectiveness of the primary treatment of the patient's cancer or preclude it all together. Cessation, interruption, or delays in patient treatment, or reducing the dosage of chemotherapeutic therapy, for example, may be detrimental to a subject's chances of long-term survival or control of the cancer, since the interruption, delay, reduction in dose, or cessation of chemotherapy can allow the progression of cancer within the subject. In some instances, it is well recognized that these chemotherapy-associated toxicities can be so severe and/or protracted that they are immediately life-threatening or fatal to the patient.
Currently, there are approximately twenty recognized classes of FDA-approved chemotherapeutic agents. These classifications are generalizations based upon either a common structure shared by the particular agents (i.e., structure-based classes) or upon a common identified mechanism(s) of action of the particular agents (i.e., mechanism-based classes); in many instances these classifications identify the same compounds by different classification approaches. Structural-based classes of chemotherapeutic agents include, for example: fluoropyrimidines; pyrimidine nucleosides; purines; anti-folates, platinum analogs; electrophilic alkylating agents; anthracyclines/anthracenediones; podophyllotoxins; camptothecins; hormones and hormonal analogs; enzymes, proteins, and antibodies, vinca alkaloids, taxanes and epothilones.
Mechanism-based classes of chemotherapeutic agents include, for example: antihormonals; antimirotubule agents, alkylating agents (classical and non-classical), antimetabolites, topoisomerase inhibitors, antivirals, and miscellaneous cytotoxic and cytostatic agents.
Taxane chemotherapeutic agents have been used to treat subjects with breast, ovarian, lung, bladder, and esophageal cancer, among others. Representatives of taxanes include paclitaxel, including without limitation, e.g., taxol, abraxane, and the like, and analogs thereof, including, without limitation, polyglutamylated forms of paclitaxel (Xyotax™), liposomal paclitaxel (Tocosol™), and docetaxel and analogs and formulations thereof. However, the administration of taxanes, for example, is commonly limited due to the development of serious and potentially life-threatening toxicities. In particular, the clinical use of taxanes frequently involves delay, modification, or discontinuance of use due to chemotherapy-associated toxicities including toxic disorders of peripheral nerve systems (including chemotherapy-induced peripheral neuropathy) resulting in numbness, burning, pain, paresthesias, dysesthesias, sensory loss, weakness, paralysis, arthralgia, myalgia, as well as other toxicities and Adverse Events (including, for example, hepatotoxicity and myelosuppression).
Platinum analog chemotherapeutic agents have been used to treat subjects with lung, head, neck, ovary, esophagus, bladder, testis, and other cancers. By way of non-limiting example, the valence of the platinum ligand contained therein may be platinum II or platinum IV. The platinum medicaments or platinum compounds of the present invention include, in a non-limiting manner, cisplatin, oxaliplatin, carboplatin, satraplatin, and derivatives thereof. Like the taxanes and other chemotherapeutic drugs, platinum analogs are associated with a number of toxicities, including nephrotoxicity, bone marrow suppression, neurotoxicity, nausea, vomiting, and others.
Amifostine (Ethyol®) and 2-mercapto ethane sulfonate sodium are FDA-approved cytoprotective agents for use in preventing and mitigating chemotherapy agent-associated Adverse Events. Amifostine is currently approved to help prevent cisplatin-induced nephrotoxicity. Problematically, however, amifostine administration has been observed to result in increased intrinsic adverse effects, such as nausea, vomiting, and severe hypotension and has not been shown to reduce or prevent neurotoxicity. 2-mercapto ethane sulfonate sodium, also known as mesna, is used to help prevent hemorrhagic toxicity to the uroepithelial tract (e.g., primarily ureters, urethra and bladder) associated with the administration of oxazaphosphorine chemotherapy, particularly ifosphamide and, less commonly, cyclophosphamide. Mesna administration, even to healthy volunteers, has been observed to result in various adverse chemotherapy-associated Adverse Events including, for example, nausea, vomiting, hypotension, pain, and diarrhea. See, e.g. Physicians Desk Reference (PDR) and American Hospital Formulary Service (AHFS).
There remains an unmet need for chemoprotective agents and compositions and methods of their administration that are optimally capable of reducing, preventing, mitigating, and/or delaying chemotherapy-associated toxicities, and which also do not result in either the addition of, or the augmentation of medically-unacceptable adverse effects that may otherwise limit or interfere with the safety and utility of the chemoprotectant agent in the subjects.
Ideal properties of a chemoprotective agent, composition, and/or regime include: (i) maximum reduction, prevention, mitigation, and/or delay in onset of chemotherapy-associated toxicities (and associated treatment interruptions, delays or dose modifications due to such toxicities); (ii) a lack of interference with anti-tumor activity and lack of tumor desensitization to cytotoxic effects of chemotherapy; (iii) a safety profile that is medically acceptable; (iv) exploitation of biochemical and pharmacological mechanisms to reduce, prevent, mitigate, and/or delay chemotherapy-associated toxicity; and (v) increases in chemotherapeutic index by allowing increases in dose, frequency, and/or duration of primary chemotherapy treatment. If a chemoprotective agent is capable of increasing the therapeutic index of an active, but otherwise toxic, chemotherapy drug, composition, and/or regimen it may lead to significant benefit to the subject by increasing tumor response rate, increasing time to tumor progression, and overall patient survival.
The inventor has previously disclosed the use of, for example, 2,2′-dithio-bis ethane sulfonate and other dithioethers: (i) to prevent and decrease nephrotoxicity (see, for example, U.S. Pat. Nos. 5,789,000; 5,866,169; 5,866,615; 5,866,617; 5,902,610) and (ii) to increase the therapeutic index of antineoplastic agents (see, for example, U.S. Pat. No. 6,037,336). Disodium 2,2′-dithio-bis ethane sulfonate has been referred to as dimesna, Tavocept®, and BNP7787 in the literature.
The present invention provides methods, as well as compositions and formulations and methods for their administration, to achieve higher degrees of patient safety and patient benefit while maintaining or increasing the therapeutic index and preventing and reducing chemotherapy-associated toxicities, including those toxicities described in the above-noted patents and patent applications. By significantly increasing the degree of safety of the patient's overall treatment with chemotherapy and reducing adverse physiological responses to chemotherapeutic pharmacological intervention, the methods, compositions and formulations of this invention will, for example: (i) allow physicians to administer increased dose levels of chemotherapeutic agents, (ii) allow administration of chemotherapeutic agents more frequently, i.e., with shorter time intervals between treatment or actual treatment time; (iii) allow increases in the number of chemotherapy treatments by the prevention of cumulative toxicities; (iv) any combination of numbers (i)-(iii) above, and/or (v) allow reduced numbers of instances of dose modifications, treatment interruptions or delays, or discontinued treatments, alone or in combination with beneficial patient outcomes, as described in numbers (i)-(iv) above.